COMPARATIVE CYTOTOXICITY OF OXALIPLATIN AND CISPLATIN IN NONSEMINOMATOUS GERM-CELL CANCER CELL-LINES

Approximately 70-80% of patients with metastatic testicular cancer wil l become disease free with cisplatin-based chemotherapy and most of th ese patients will be long-term survivors. Despite these impressive res ults, the two limitations of cisplatin are its severe and potentially long-term side-effects, and the emergence of drug resistance which pre vents a small proportion of these patients from achieving long-term re mission. Oxaliplatin has an improved toxicity profile compared to cisp latin and contains the diaminocyclohexane (DACH) substituent known to be correlated with a lack of cross-resistance with cisplatin. A phase II study has shown interesting activity when used in combination with cisplatin in cisplatin-refractory testicular cancer patients. Here we report the results of the first in vitro study investigating whether o xaliplatin as a single agent exhibits cross-resistance to cisplatin in a panel of non-seminomatous germ cell tumor (NSGCT) cell lines using short and long-term drug exposures in a five-day sulfhodamine B in vit ro cytotoxicity assay. Oxaliplatin cytotoxicity was significantly supe rior to cisplatin in cell lines with both acquired (H12DDP) and intrin sic (1777NRp Cl-A) intermediate level resistance to cisplatin. Followi ng 24h or 96h drug exposure the fold resistance in H12DDP and 1777NRp Cl-A was 1.7-2.2 with oxaliplatin compared to 3.9-6.1 with cisplatin. The cytotoxic activity of oxaliplatin was not significantly different from that of cisplatin in cisplatin-senstive cell lines or in cell lin es with a high level (10-20 fold) of cisplatin resistance. The results of this study suggest that further preclinical studies in NSGCT are o f interest, particularly in combination with cisplatin, ifosfamide and etoposide. Furthermore, the in vitro results support the use of an ox aliplatin administration schedule giving prolonged drug exposure, such as the flat or circadian rhythm-modulated schedule already under inve stigation for oxaliplatin.